Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing 211198, China.
Bioorg Med Chem. 2018 May 1;26(8):1665-1674. doi: 10.1016/j.bmc.2018.02.014. Epub 2018 Feb 13.
In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.
在我们努力开发用于治疗阿尔茨海默病的有效多靶标配体的过程中，发现咪康唑具有 BuChE-IDO1 双重靶标抑制作用。Morris 水迷宫试验表明，咪康唑明显改善了东莨菪碱引起的认知功能障碍。此外，它在原发性肝毒性评价中表现出良好的安全性。基于这些结果，我们设计、合成并评价了一系列咪康唑衍生物作为 BuChE-IDO1 双重靶标抑制剂。在所合成的 12 个化合物中，化合物 5i 和 5j 在酶活性评价中表现出最好的活性，因此被选择进行后续的行为学研究，结果表明这两个化合物的效果明显优于他克林。同时，化合物 5i 和 5j 没有明显的肝毒性。这些结果表明，咪康唑类似物为进一步开发用于治疗阿尔茨海默病的新型 BuChE-IDO1 双重靶标抑制剂提供了一个有吸引力的起点。
